1. Field of the Invention
The present invention relates to a method for preparing a glucosamine compound, and to a compound thus obtained.
2. Description of the Background
As is known, glucosamine (2-amino-2-deoxyglucose; chitosamine; GluNH2) is a component of mucoproteins and mucopolysaccharides. It is usually obtained from chitin and is isolated as the hydrochloride.
Glucosamine sulphate is a drug that is well known and widely used in the treatment of rheumatic fever, arthritic and arthrosic complaints, both acute and chronic, and in the treatment of pathological conditions originating from metabolic disorders of osteoarticular tissue. Its synthesis was described at the end of 1898 by Breuer (Chem. Ber. 31, 2197). However, its physicochemical properties are such that it is relatively difficult to handle and occasionally unstable. The main problems are derived from its high hygroscopicity.
U.S. Pat. No. 4,642,340 teaches how to overcome this drawback by using a presumed mixed salt of formula A:[GluNH3+]2.2Na+.SO42−.2Cl−  Awhich is in the form of crystalline powder, melts at more than 300° C., is stable under ambient conditions and has pharmacological properties that are substantially identical to those of glucosamine sulphate.
The said document also describes the preparation of the said presumed mixed salt A, by:    (a) dissolving, with stirring, anhydrous sodium chloride in 5.5-7.5 parts by weight of distilled water for each part of sodium chloride at a temperature of from 50° C. to 70° C.;    (b) dissolving, with stirring, in the solution obtained in step (a), a stoichiometric amount of glucosamine sulphate at a temperature of from 35° C. to 45° C.;    (c) precipitating the presumed mixed salt A by adding a precipitating liquid that is water-miscible and in which the presumed mixed salt A has a solubility not greater than 0.1% (w/v), this step being performed with stirring at a temperature of from 40° C. to 50° C.;    (d) completing the precipitation by reducing the temperature of the mixture; and    (e) recovering the presumed precipitated mixed salt A.
The precipitating liquid used in step (c) is acetone, ethanol, acetonitrile, tetrahydrofuran or dioxane.
A similar method is described in U.S. Pat. No. 5,847,107. According to this method, the said presumed mixed salt A is obtained by:    (a) dissolving glucosamine hydrochloride and sodium sulphate, in stoichiometric amounts, in water; and    (b) precipitating the presumed mixed salt A by adding a precipitating liquid that is water-miscible.
In this case also, the precipitating liquid used is acetone, ethanol, acetonitrile, tetrahydrofuran or dioxane.
Another similar method is described in EP-A-0 214 642. According to this method, the said presumed mixed salt A and other similar products are obtained by:    (a) forming glucosamine sulphate from glucosamine and sulphuric acid in water;    (b) forming the presumed mixed salt A by adding an approximately stoichiometric amount of an alkali metal halide or alkaline-earth metal halide; and    (c) precipitating the presumed mixed salt A by adding a water-soluble solvent.
The precipitating solvents mentioned are ethanol, acetone and acetonitrile.
According to U.S. Pat. No. 5,902,801, the product present on the market is not thought to be a true mixed salt A, but rather a simple stoichiometric mixture of glucosamine hydrochloride and sodium sulphate (column 1, lines 23-29). This document describes a compound that purports to be novel and to be the true mixed salt A. According to this document, the true mixed salt A is that obtained by (column 3, lines 5-19):    (a) placing stoichiometric amounts of glucosamine hydrochloride and sodium sulphate in contact in a sufficient amount of water to have a solids concentration of from about 15 to 40% by weight (this step takes from 15 minutes to 2 hours and is carried out at a temperature of from about 20° C. to about 40° C.); and    (b) removing the water by freeze-drying at a pressure below 800 milliTorr, preferably from 300 to 500 milliTorr, and at a temperature from −60° C. to 0° C. and preferably from −40° C. to −5° C.
However, the water is not totally removed and the mixed salt A thus obtained contains from 3 to 5% by weight of water (column 2, lines 20-24).
The abovementioned known methods thus involve the use of starting materials in one of the exact stoichiometric ratios given below:[GluNH2]2.H2SO4+2NaCl→A  Eq. 1[GluNH2.HCP]2+H2SO4→A  Eq. 2
A person skilled in the art will readily appreciate that the abovementioned prior art methods have considerable drawbacks.
Specifically, in the methods of U.S. Pat. No. 4,642,340, U.S. Pat. No. 5,847,107 and EP-A-0 214 642, the precipitation requires the use of organic solvents and this obliges the application of specific safety standards on account of their flammability and explosiveness. In addition, a specific treatment of the wastes is necessary before discharging. This therefore involves factors that, in addition to having an impact on the safety of the industrial production, also involve increases in the production costs. Finally, a further drawback is given by the fact that the organic solvents cannot be completely removed from the presumed mixed salt A either during the drying operation.
As regards the freeze-drying process required in the method of U.S. Pat. No. 5,902,801, in addition to being expensive, it does not allow the impurities present in the initial solution to be removed. The mixed salt A thus obtained actually retains all the abovementioned impurities. To overcome this drawback, the glucosamine hydrochloride and the sodium sulphate will have to be very pure and, therefore, very expensive. Finally, small amounts of water also tend to remain in the mixed salt A in the freeze-drying process.